| Purpose:To describe and analyze the clinical pathological features and survival of patients with advanced HCCwho received oral Sorafenib.Material and methods.We retrospectivelycollected the clinical pathological data of 74 advanced HCC patients with definite pathological diagnosis and history of oral Sorafenib in our hospital from January 2005 to January 2013. We made Univariate analysis of PFS and OS, and analyzed the prognostic factors of survival by SPSS 19.9. Results:(1) 74 cases of patients with advanced HCC were treated with sorafenib, and the median follow-up time was 535 days,64 cases were male and 10 cases were female (6.4:1). The median age was 62 years, patients with hepatitis C, better KPS score and without family history of cancer had relatively longer PFS; patients with hepatitis C, AFP< 400, KPS score>90, well-moderatelydifferentiated tumor and patients without smoking, alcohol and family history of cancer had relatively longer OS. Family history of cancer, hepatitis B, KPS 70-80, poorly differentiated tumor were adverse prognostic factors of the survival; alcohol, hepatitis B, KPS 70-80 were adverse prognostic factors during the time of oral Sorafenib; (2)Immunofiuorescence staining showed that HIF1αand YAP accumulated in the nucleusof tissue samples, and the nucleus positive rate were much higher in patients who had poorer clinical benefits from Sorafenib, however, HIF1αand YAP accumulated in the cytoplasm in patients with better clinical benefits; (3)In normal cultured liver cells, the HIF1αand YAP had a small amount of expression, but the coincidence rate was low and mainly concentrated in the cytoplasm, with low nuclei positive rate; (4) HIF 1α and YAP mainly concentrated in the cytoplasm and nuclei positive ratewere further reduced when the liver cancer cells were under normal oxygen environment combined with Sorafenib; (5) HIF 1α and YAP mainly concentrated in the nucleus and nuclei positive rate were elevated when the liver cancer cells were under hypoxia environment combined with Sorafenib; (6) The expressionof HIF 1α and YAPincreased and mainly concentrated in the nucleusunder hypoxia environment, suggested that hypoxia may contribute to drug resistance; (7) When YAP mainly concentrated in the nucleus of liver cancer, the related parameters of EMT:E-cadherin declined, N-cadherin and Vimentinincreased, predicted that the phenomena of transportion of YAPto the nucleuswas accosiated with the malignant degree and the invasionof tumor cells; (8) The cytotoxicity test of normal cultured liver cells suggested that hypoxic condition may resist the antitumor effect of Sorafenib, and promote the proliferation of tumor cells; (9) After the silencing of HIF 1α, we made hypoxia environment and Sorafenib to the liver cancer cells, found that the expression level of YAP and the migration to the nucleus phenomena showed no significant change, but the cytotoxicity test showed that the tolerance of liver cancer cells to Sorafenib was lowered; (10)HIF 1α and YAP may play synergy role in the mechanisms of hypoxia induced drug resistance.Conclusion:(1)Through the analysis of patients with advanced HCCwho received oral Sorafenib, we found some clinical pathological factors related with the survival and effction of Sorafenib, which had some guiding significance for the management; (2)Hypoxia environment could resist the antitumoreffect Sorafenib and inducedrug resistance; (3) The migration to the nucleus of YAP under hypoxia environment had an important relationship with drug resistance and prognosis; (4) The gene silencing of HIF 1αincreased the sensitivityto Sorafenib; (5) HIF 1α and YAP may play synergy role in the mechanisms of hypoxia induced drug resistance. |
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